Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein

Prion diseases are fatal neurodegenerative disorders in man and animal asso ciated with conformational conversion of a cellular prion protein (PrPc) in to the pathologic isoform (PrPSc). The function of PrPc and the tertiary st ructure of PrPSc are unclear. Various data indicate which parts of PrP migh t control the species barrier in prion diseases and the binding of putative factors to PrP. To elucidate these features, we analyzed the evolutionary conservation of the prion protein. Here, we add the primary PrP structures of 20 ungulates, three rodents, three carnivores, one maritime mammal, and nine birds. Within mammals and birds we found a high level of amino acid se quence identity, whereas between birds and mammals the overall homology was low. Various structural elements were conserved between mammals and birds. Using the CONRAD space-scale alignment, which predicts conserved and varia ble blocks, we observed similar patterns in avian and mammalian PrPs, altho ugh 130 million years of separate evolution lie in between. Our data suppor t the suggestion that the repeat elements might have expanded differently w ithin the various classes of vertebrates. Of note is the N-terminal part of PrP (amino acid residues 23-90), which harbors insertions and deletions, w hereas in the C-terminal portion (91-231) mainly point mutations are found. Strikingly, we found a high level of conservation of sequences that are no t part of the structured segment 121-231 of PrPc and of the structural elem ents therein, e.g. the N-terminal region from amino acid residue 23-90 and the regions located upstream of alpha-helices 1 and 3. (C) 1999 Academic Pr ess.